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human intestinal organoid

James R Bayrer, Hongtao Wang, Roy Nattiv, Miyuki Suzawa, Hazel S Escusa, Robert J Fletterick, Ophir D Klein, David D Moore, Holly A Ingraham
Epithelial dysfunction and crypt destruction are defining features of inflammatory bowel disease (IBD). However, current IBD therapies targeting epithelial dysfunction are lacking. The nuclear receptor LRH-1 (NR5A2) is expressed in intestinal epithelium and thought to contribute to epithelial renewal. Here we show that LRH-1 maintains intestinal epithelial health and protects against inflammatory damage. Knocking out LRH-1 in murine intestinal organoids reduces Notch signaling, increases crypt cell death, distorts the cellular composition of the epithelium, and weakens the epithelial barrier...
October 10, 2018: Nature Communications
Konrad Aden, Kareen Bartsch, Joseph Dahl, Martin A M Reijns, Daniela Esser, Raheleh Sheibani-Tezerji, Anupam Sinha, Felix Wottawa, Go Ito, Neha Mishra, Katharina Knittler, Adam Burkholder, Lina Welz, Johan van Es, Florian Tran, Simone Lipinski, Nassim Kakavand, Christine Boeger, Ralph Lucius, Witigo von Schoenfels, Clemens Schafmayer, Lennart Lenk, Athena Chalaris, Hans Clevers, Christoph Röcken, Christoph Kaleta, Stefan Rose-John, Stefan Schreiber, Thomas Kunkel, Björn Rabe, Philip Rosenstiel
BACKGROUND & AIMS: RNase H2 is a holoenzyme comprising 3 subunits (ribonuclease H2 subunits A, B, and C) that cleaves RNA:DNA hybrids and removes misincorporated ribonucleotides from genomic DNA via ribonucleotide excision repair. Ribonucleotide incorporation by eukaryotic DNA polymerases occurs during every round of genome duplication and produces the most frequent type of naturally occurring DNA lesion. We investigated whether intestinal epithelial proliferation requires RNase H2 function and whether RNase H2 activity is disrupted during intestinal carcinogenesis...
September 28, 2018: Gastroenterology
Katia Beaudry, Marie-Josée Langlois, Amélie Montagne, Sébastien Cagnol, Julie C Carrier, Nathalie Rivard
The Ras/mitogen-activated protein kinase (MAPK) pathway controls fundamental cellular processes such as proliferation, differentiation, and apoptosis. The dual-specificity phosphatase 6 (DUSP6) regulates cytoplasmic MAPK signaling by dephosphorylating and inactivating extracellular signal-regulated kinase (ERK1/2) MAPK. To determine the role of DUSP6 in the maintenance of intestinal homeostasis, we characterized the intestinal epithelial phenotype of Dusp6 knockout (KO) mice under normal, oncogenic, and proinflammatory conditions...
October 1, 2018: Journal of Cellular Physiology
Anna S Lehle, Henner F Farin, Benjamin Marquardt, Birgitta E Michels, Thomas Magg, Yue Li, Yanshan Liu, Maryam Ghalandary, Katja Lammens, Sebastian Hollizeck, Meino Rohlfs, Fabian Hauck, Raffaele Conca, Christoph Walz, Batia Weiss, Atar Lev, Amos J Simon, Olaf Groß, Moritz M Gaidt, Veit Hornung, Hans Clevers, Nadine Yazbeck, Rima Hanna-Wakim, Dror S Shouval, Neil Warner, Raz Somech, Aleixo M Muise, Scott S Snapper, Philip Bufler, Sibylle Koletzko, Christoph Klein, Daniel Kotlarz
Caspase-8 (CASP8) is a protease that initiates apoptosis and regulates inflammation and immune responses. We identified germline mutations in CASP8 in 3 unrelated patients with infant-onset inflammatory bowel disease: 2 patients were homozygous for the mutation 710A>G, p.Q237R, which resulted in reduced protein expression, and 1 patient carried the mutation 793C>T, p.R265W. We isolated peripheral blood mononuclear cells from our index patient and observed defects in T- and B-cell maturation, proliferation, and/or activation...
September 26, 2018: Gastroenterology
James Clinton, Penney McWilliams-Koeppen
Organoids are primary patient-derived micro tissues grown within a three-dimensional extracellular matrix that better represents in vivo physiology and genetic diversity than existing two-dimensional cell lines. Organoids rely on the self-renewal and differentiation of tissue-resident stem cells that expand in culture and self-organize into complex three-dimensional structures. Depending on the tissue, organoids typically lack stromal, vascular, neural, and immune cells but otherwise can contain cells from all the respective tissue-specific cell lineages found in vivo...
September 28, 2018: Current Protocols in Cell Biology
Neil O'Donnell, Irina A Okkelman, Peter Timashev, Tatyana I Gromovykh, Dmitri B Papkovsky, Ruslan I Dmitriev
Quantitative measurement of pH and metabolite gradients by microscopy is one of the challenges in the production of scaffold-grown organoids and multicellular aggregates. Herein, we used the cellulose-binding domain (CBD) of the Cellulomonas fimi CenA protein for designing biosensor scaffolds that allow measurement of pH and Ca2+ gradients by fluorescence intensity and lifetime imaging (FLIM) detection modes. By fusing CBD with pH-sensitive enhanced cyan fluorescent protein (CBD-ECFP), we achieved efficient labeling of cellulose-based scaffolds based on nanofibrillar, bacterial cellulose, and decellularized plant materials...
September 25, 2018: Acta Biomaterialia
Hayley Derricott, Lisa Luu, Wai Yee Fong, Catherine S Hartley, Luke J Johnston, Stuart D Armstrong, Nadine Randle, Carrie A Duckworth, Barry J Campbell, Jonathan M Wastling, Janine L Coombes
The in vitro 3D culture of intestinal epithelium is a valuable resource in the study of its function. Organoid culture exploits stem cells' ability to regenerate and produce differentiated epithelium. Intestinal organoid models from rodent or human tissue are widely available whereas large animal models are not. Livestock enteric and zoonotic diseases elicit significant morbidity and mortality in animal and human populations. Therefore, livestock species-specific models may offer novel insights into host-pathogen interactions and disease responses...
September 26, 2018: Cell and Tissue Research
Ellen E Higginson, Girish Ramachandran, Aruna Panda, Steven T Shipley, Edwin H Kriel, Louis J DeTolla, Michael Lipsky, Darren J Perkins, Rosangela Salerno-Goncalves, Marcelo B Sztein, Marcela F Pasetti, Myron M Levine, Sharon M Tennant
A notable proportion of Salmonella -associated gastroenteritis in the United States is attributed to Salmonella enterica serovar Typhimurium. We have previously shown that live-attenuated S. Typhimurium vaccine candidate CVD 1921 (I77 Δ guaBA Δ clpP ) was safe and immunogenic in rhesus macaques, but was shed for an undesirably long time post-immunization. In mice, occasional mortality post-vaccination was also noted (approximately 1 in every 15 mice). Herein we describe a further attenuated vaccine candidate strain harboring deletions in two additional genes, htrA and pipA We determined that S...
September 24, 2018: Infection and Immunity
Xiaogang Hou, David F Chang, Andrew Trecartin, Erik R Barthel, Christopher R Schlieve, Mark R Frey, Kathryn L Fowler, Tracy C Grikscheit
NEW FINDINGS: What is the central question of this study? Tissue-engineered small intestine (TESI) was previously generated in vivo by immediate implantation of organoid units (OU) derived from both mouse and human donor intestine. Although immediate transplantation of OU into patients shows promise as a potential future therapy, some critically ill patients may require delayed transplantation. What is the main finding and its importance? Unlike enteroids that consist of isolated intestinal crypts, short and long-term cultured organoid units are composed of epithelial and mesenchymal cells derived from mouse or human intestine...
September 19, 2018: Experimental Physiology
Jessica L Forbester, Emily A Lees, David Goulding, Sally Forrest, Amy Yeung, Anneliese Speak, Simon Clare, Eve L Coomber, Subhankar Mukhopadhyay, Judith Kraiczy, Fernanda Schreiber, Trevor D Lawley, Robert E W Hancock, Holm H Uhlig, Matthias Zilbauer, Fiona Powrie, Gordon Dougan
Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar Typhimurium SL1344 infection. A combination of transcriptomics, bacterial invasion assays, and imaging suggests that IL-22-induced antimicrobial activity is driven by increased phagolysosomal fusion in IL-22-pretreated cells...
October 2, 2018: Proceedings of the National Academy of Sciences of the United States of America
Yuli Wang, Raehyun Kim, Shee-Hwan J Hwang, Johanna Dutton, Christopher E Sims, Nancy L Allbritton
In vitro models of the human intestinal epithelium derived from primary stem cells are much needed for the study of intestinal immunology in health and disease. Here, we describe an intestinal monolayer cultured on a porous membrane with accessible basal and apical surfaces for assay of intestinal cytokine production in response to stimuli. The system was composed of a differentiated, confluent epithelial monolayer derived from human primary stem cells obtained from small or large intestine. Interleukin 8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) were the most abundant inflammatory cytokines produced by the intestinal epithelium...
October 2, 2018: Analytical Chemistry
Yuan Li, Christoffer Soendergaard, Fredrik Holmberg Bergenheim, David M Aronoff, Ginger Milne, Lene Buhl Riis, Jakob Benedict Seidelin, Kim B Jensen, Ole Haagen Nielsen
BACKGROUND: Inhibition of tumor necrosis factor-α (TNF) signaling is beneficial in the management of ulcerative colitis (UC), but up to one-third of patients do not have a clinical response of relevance to TNF inhibitors during induction therapy (i.e. primary non-responders [PNRs]). Through production of prostaglandins (PGs) and thromboxanes, cyclooxygenase-2 (COX-2) affects inflammation and epithelial regeneration and may in this way be implicated in treatment resistance to TNF inhibitors...
September 3, 2018: EBioMedicine
Johannes Schöneberg, Daphné Dambournet, Tsung-Li Liu, Ryan Forster, Dirk Hockemeyer, Eric Betzig, David G Drubin
New methods in stem cell 3D organoid tissue culture, advanced imaging and big data image analytics now allow tissue scale 4D cell biology, but currently available analytical pipelines are inadequate for handing and analyzing the resulting gigabytes and terabytes of high-content imaging data. We expressed fluorescent protein fusions of clathrin and dynamin2 at endogenous levels in genome-edited human embryonic stem cells, which were differentiated into hESC-derived intestinal epithelial organoids. Lattice Light-Sheet Imaging with adaptive optics (AO-LLSM) allowed us to image large volumes of these organoids (70µm x 60µm x 40µm xyz) at 5...
September 6, 2018: Molecular Biology of the Cell
Jennifer Barrila, Aurélie Crabbé, Jiseon Yang, Karla Franco, Seth D Nydam, Rebecca J Forsyth, Richard R Davis, Sandhya Gangaraju, C Mark Ott, Carolyn B Coyne, Mina J Bissell, Cheryl A Nickerson
Tissues and organs provide the structural and biochemical landscapes upon which microbial pathogens and commensals function to regulate health and disease. While flat two-dimensional (2-D) monolayers composed of a single cell type have provided important insight into understanding host-pathogen interactions and infectious disease mechanisms, these reductionist models lack many essential features present in the native host microenvironment that are known to regulate infection, including three-dimensional (3-D) architecture, multicellular complexity, commensal microbiota, gas exchange and nutrient gradients, and physiologically relevant biomechanical forces (e...
September 4, 2018: Infection and Immunity
Stephanie Jaeckel, Markus Kaller, Rene Jackstadt, Ursula Götz, Susanna Müller, Sophie Boos, David Horst, Peter Jung, Heiko Hermeking
The gene encoding the transcription factor TFAP4/AP4 represents a direct target of the c-MYC oncoprotein. Here, we deleted Ap4 in ApcMin mice, a preclinical model of inherited colorectal cancer. Ap4 deficiency extends their average survival by 110 days and decreases the formation of intestinal adenomas and tumor-derived organoids. The effects of Ap4 deletion are presumably due to the reduced number of functional intestinal stem cells (ISCs) amenable to adenoma-initiating mutational events. Deletion of Ap4 also decreases the number of colonic stem cells and increases the number of Paneth cells...
September 3, 2018: Nature Communications
Isabella Dotti, Azucena Salas
Inflammatory bowel disease (IBD) is a chronic remitting disorder with increasing incidence worldwide. The intestinal epithelial barrier plays a major role in IBD, contributing to its pathogenesis, evolution, and perpetuation over time. Until recently, studies focused on exploring the role of the intestinal epithelium in IBD were hampered by the lack of techniques for the long-term culturing of human primary epithelial cells ex vivo. Recently, however, a methodology for generating stable human 3D epithelial cultures directly from adult intestinal stem cells was established...
August 29, 2018: Inflammatory Bowel Diseases
Holly M Poling, David Wu, Nicole Brown, Michael Baker, Taylor A Hausfeld, Nhan Huynh, Samuel Chaffron, James C Y Dunn, Simon P Hogan, James M Wells, Michael A Helmrath, Maxime M Mahe
The natural ability of stem cells to self-organize into functional tissue has been harnessed for the production of functional human intestinal organoids. Although dynamic mechanical forces play a central role in intestinal development and morphogenesis, conventional methods for the generation of intestinal organoids have relied solely on biological factors. Here, we show that the incorporation of uniaxial strain, by using compressed nitinol springs, in human intestinal organoids transplanted into the mesentery of mice induces growth and maturation of the organoids...
June 2018: Nature Biomedical Engineering
Katie L Sinagoga, Heather A McCauley, Jorge O Múnera, Nichole A Reynolds, Jacob R Enriquez, Carey Watson, Hsiu-Chiung Yang, Michael A Helmrath, James M Wells
Enteroendocrine cells (EECs) are a minor cell population in the intestine yet they play a major role in digestion, satiety and nutrient homeostasis. Recently developed human intestinal organoid models include EECs, but their rarity makes it difficult to study their formation and function. Here, we used the EEC-inducing property of the transcription factor NEUROG3 in human pluripotent stem cell-derived human intestinal organoids and colonic organoids to promote EEC development in vitro An 8-h pulse of NEUROG3 expression induced expression of known target transcription factors and after 7 days organoids contained up to 25% EECs in the epithelium...
October 1, 2018: Development
Aarti Sawant-Basak, A David Rodrigues, Matthew Lech, Regis Doyonnas, Marion Kasaian, Bhagwat Prasad, Nikolaos Tsamandouras
Intestinal disposition of small molecules involves interplay of drug-metabolizing enzymes, transporters, and host-microbiome, which has spurred the development of in vitro intestinal models derived from primary tissue sources. Such models have been bio-engineered from intestinal crypts, mucosal extracts, iPSC-derived organoids, and human intestinal tissue. The present mini-review discusses the utility and limitations of these human derived models in support of small molecule drug metabolism and disposition...
August 20, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Emily C Moorefield, R Eric Blue, Nancy L Quinney, Martina Gentzsch, Shengli Ding
BACKGROUND: Conditional reprogramming has enabled the development of long-lived, normal epithelial cell lines from mice and humans by in vitro culture with ROCK inhibitor on a feeder layer. We applied this technology to mouse small intestine to create 2D mouse intestinal epithelial monolayers (IEC monolayers) from genetic mouse models for functional analysis. RESULTS: IEC monolayers form epithelial colonies that proliferate on a feeder cell layer and are able to maintain their genotype over long-term passage...
August 15, 2018: BMC Cell Biology
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